The cyclic nucleotides 5′-3′ cyclic adenosine monophosphate (cAMP) and 5′-3′ cyclic guanosine monophosphate (cGMP) are second messenger molecules, relaying signals from receptors on the cell surface to target molecules inside the cell. The cyclic nucleotide phosphodiesterases (PDEs) are a group of enzymes (which can be localized to different cellular compartments) that hydrolyze the phosphodiester bond of cyclic nucleotides and thereby inactivate their function. PDEs can therefore play important roles in signal transduction by modulating the localization, amplitude, and duration of cyclic nucleotide signaling within the cell.
PDEs comprise at least eleven families: PDE1-PDE11, each categorized by distinct molecular, kinetic, regulatory, and inhibitory properties. PDE family members are differentially expressed in various tissues and can localize to distinct sub-cellular domains. This diversity enables PDEs to modulate local intracellular cAMP and cGMP gradients in response to discrete external stimuli (Conti and Beavo, Annu. Rev. Biochem. 2007, 76, 481-511).
Among the PDE families, PDE1 is unique in its requirement for full activation by calcium (Ca2+) and calmodulin (CaM). Calcium enters the cell and forms a complex with CaM. Binding of the Ca2+/CaM complexes to multiple domains near the N-terminus of PDE1 can result in full phosphodiesterase activity. PDE1 is therefore a point of convergence and integration for multiple signaling pathways that regulate numerous downstream targets and cellular events (Sharma et al., Int. J. Mol. Med. 2006, 18, 95-105).
The PDE1 family comprises three genes (pde1a, pde1b, and pde1c), and each encodes multiple isoforms via alternative splicing and differential transcription. All PDE1 enzymes appear to hydrolyze both cAMP and cGMP, although they can differ in their relative affinities for each (Bender and Beavo, Pharmacol. Rev. 2006, 58, 488-520).
PDE1 is expressed in many tissues, underscoring a role in many physiological processes. Regions of PDE expression include, but are not limited to, the heart, lungs, veins and arteries, smooth muscle, skeletal muscle, skin, adrenal gland, thyroid, pancreas, esophagus, stomach, small intestine, colon, liver, leukocytes, testis, ovary, bladder, kidney, and the nervous system. In the brain, PDE1 isoforms are expressed in the cerebral cortex, frontal lobe, hippocampus, cerebellum, and amygdala, regions involved in memory formation and other cognitive processes. PDE1b expression, in particular, correlates closely with brain regions showing high levels of dopaminergic innervation. In the cardiovascular system, PDE1 appears to play a central role in organizing cAMP microdomains and mediating hormonal specificity in cardiac cells (Maurice et al., Mol. Pharm. 2003, 64, 533-546). Indeed, human PDE1b is highly expressed in numerous cardiovascular regions, including the pericardium, heart atrium (left), heart apex, Purkinje fibers, and pulmonic valve.
More generally, cyclic nucleotide signaling pathways, including those involving PDE1, are implicated in numerous pathological processes (Keravis and Lugnier, Br. J. Pharmacol. 2012, 165, 1288-1305). For example, alterations in these pathways have been implicated in various disorders of the brain, including depression, schizophrenia and cognitive disorders. Inhibiting PDE1 activity in the nervous system, for example, can increase cAMP or cGMP levels and consequently induce expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. Based on such properties, PDE1 inhibitors are promising therapeutic candidates in treating many CNS disorders and associated cognitive impairments. Similarly, PDE1 enzymes and cyclic nucleotides are emerging as key mediators of pathological processes that underlie many vascular disorders, including hypertension, myocardial infarction, and heart failure (Miller et al., Basic Res. Cardiol. 2011, 106, 1023-1039 and Miller et al, Circ. Res. 2009, 105, 956-964). In addition, PDE1 is implicated in the development and progression of renal disease, where cAMP and cGMP regulate a variety of signaling pathways, including those that modulate mitogenesis, inflammation, and extracellular matrix synthesis (Wang et al., Kidney Int. 2010, 77. 129-140; Cheng et al., Soc. Exp. Biol. Med. 2007, 232, 38-51 and Dousa, Kidney Int. 1999, 55, 29-62).
Accordingly, there is a need to develop treatments for CNS and other disorders, as well as disorders that are due, at least in part, to an aberration or dysregulation of an intracellular signaling pathway regulated by PDE1.
Various small-molecule PDE1 enzyme inhibitors have been reported e.g., imidazopyrazolopyrimidinones (Intra-Cellular Therapeutics Intl. Pat. Appl. Publ. WO 2012171016, Dec. 13, 2012), pyrrolopyrimidinones (Intra-Cellular Therapeutics Intl. Pat. Appl. Publ. WO 2011153138, Dec. 8, 2011; Intl. Pat. Appl. Publ. WO 2011153136, Dec. 8, 2011; Intl. Pat. Appl. Publ. WO 2011153135, Dec. 8, 2011; Intl. Pat. Appl. Publ. WO 2011153129, Dec. 8, 2011), imidazopurinone (Intra-Cellular Therapeutics Intl. Pat. Appl. Publ. WO 2010132127, Nov. 18, 2010), pyrazolopyrimidinedione (Intra-Cellular Therapeutics Intl. Pat. Appl. Publ. WO 2010098839, Sep. 2, 2010), pyrazolopyrimidinone (Intra-Cellular Therapeutics Intl. Pat. Appl. Publ. WO 2010065153, Jun. 10, 2010; WO 2010065149, Jun. 10, 2010; Intl. Pat. Appl. Publ. WO 2009075784, Jun. 18, 2009).
However, there remains a need for potent PDE1 inhibitors with desirable pharmaceutical properties. It is therefore desirable to develop improved PDE1 inhibitors showing higher potency, greater specificity, and better side effect profiles. The present invention meets these and other needs in the art by disclosing substituted pyridine-fused and azolopyrimidin-5-(6h)-one compounds as potent and well-tolerated PDE1 inhibitors.